Glucocorticoids influence performance on declarative memory tasks and tasks of memory for emotional information. The cognitive effects of exogenous glucocorticoids depend on dose, the time period between administration and testing, and the time of testing within the diurnal pattern of cortisol secretion. Additionally, glucocorticoid administration can influence mood, and with chronic administration glucocorticoids may lead to the development of mania or depression. [unreadable] A potential mechanism by which glucocorticoids may influence emotional behavior is via their effects on the neurophysiological activity of the amygdala and prefrontal cortical structures known to participate in emotional processing. Human imaging studies indicate that the amygdala, ventral medial prefrontal, and other prefrontal cortical areas are activated during tasks requiring processing of affective stimuli. These data converge with lesion analysis and electrophysiological studies performed in humans and experimental animals that indicate these structures participate in brain circuits that process emotional information. These brain structures contain dense concentrations of glucocorticoid mRNA and receptors. Increased glucocorticoids appear to potentiate activation of the amygdala and affect processing of emotionally laden stimuli based on both experimental animal studies and correlational human studies. [unreadable] The present study investigates the influence of glucocorticoids on the hemodynamic response that occurs while processing emotionally-valenced visual stimuli known to activate the amygdala and anatomically-related areas of the prefrontal cortex (PFC) in healthy humans. Functional magnetic resonance images will be acquired during the performance of tasks that involve viewing emotionally expressive faces both before and following either hydrocortisone (synthetic cortisol) (0.15 mg/kg or 0.45 mg/kg bolus) or placebo administration. The change in the BOLD signal in structures of interest will be compared across high dose cortisol, low dose cortisol and placebo conditions. In addition, the effects of hydrocortisone on relative blood flow in the amygdala and PFC will be assessed using an arterial spin labeling (ASL) technique to measure perfusion. The findings of this study will guide future research into the effects of glucocorticoids on emotional perception in subjects with mood disorders. [unreadable] During the past one year additional subjects have been entered into the study and successfully scanned under both placebo and hydrocortisone conditions. The image data have been analyzed and show that hydrocortisone administration potentiated the amygdala, inferotemporal and lateral orbital cortex responses to fearful and sad faces. We also demonstrated differential effects between high and low dose hydrocortisone administration in the amygdala and anterior cingulate, areas that play major roles in emotional behavior and memory. The high dose in particular had an effect of increasing the left amygdala response to sad face stimuli, and of attenuating the normal habituation of amygdalar hemodynamic responses to fearful face stimuli. These findings provide important insights as to the mechanisms via which cortisol release may facilitate responses to stressors or threats, and show the differences between these responses during exposure to the amount of cortisol released during mild versus severe stress (i.e., low and high dose hydrocortisone, respectively). We also demonstrated that the neurophysiological effects of hydrocortisone differ between males and females. One manuscript has been submitted for publication and two additional manuscripts are in preparation to describe these findings.[unreadable] [unreadable] In addition, in neuropsychological studies, hydrocortisone affected the behavioral responses on the affective shifting test. These data suggest that the effects of hydrocortisone on neurophysiological responses to emotional stimuli are, in fact, functionally relevant. These data hold great potential for elucidating the cause of attentional biases toward sad stimuli seen in depression. A manuscript is in preparation to describe these effects.[unreadable] [unreadable] We also showed that major sex differences exist in the effect of hydrocortisone on face processing. Specfically, under placebo the amygdala is more responsive to sad faces in women than men. Under hydrocortisone tha men increase their responses to sad faces so that their amygdala responses resemble those of women. Since depressed individuals show both elevated cortisol and exaggerated amygdala responses to sad faces, these data may provide insights into the neural basis regarding the higher risk of depression in women versus men.[unreadable] [unreadable] We now are in the process of adding a depressed group to investigate whether differential responsiveness to glucocorticoid receptor stimulation exists in depression.